CLINICAL PRACTICE

Diagnosis and Management of Infections Caused by

Enterobacteriaceae Producing Extended-Spectrum
b-Lactamase

Audrey Amelia, Agung Nugroho, Paul N. Harijanto

Department of Internal Medicine, Faculty of Medicine, University of Sam Ratulangi - Prof. Dr. R. D. Kandou
Hospital, Manado, Indonesia.

Corresponding Author:
Audrey Amelia, MD. Division of Tropical and Infectious Diseases, Department of Internal Medicine, Faculty of
Medicine, University of Sam Ratulangi - Prof. Dr. R. D. Kandou Hospital. Jl. Raya Tanawangko, Manado 95115,
Indonesia. email: audrey_amelia@yahoo.com.au.

ABSTRAK
Resistensi bakteri terhadap antibiotik merupakan salah satu masalah yang sangat serius di seluruh
dunia yang berdampak pada meningkatnya angka morbiditas dan mortalitas, salah satunya adalah akibat
Enterobacteriaceae penghasil ESBL. Meskipun demikian, informasi mengenai penegakan diagnosis dan
penatalaksanaan infeksi ESBL-E masih terbatas. Deteksi ESBL-E memerlukan beberapa tahap yang cukup sulit
dan memerlukan waktu yang lama. Diagnosis dan penatalaksanaan infeksi akibat ESBL-E menjadi semakin
sulit karena keterbatasan metode diagnosis yang ada dan pilihan antibiotik yang dapat digunakan, bersamaan
dengan subtipe ESBL yang terus berkembang melalui proses mutasi yang beragam. Artikel ini bertujuan untuk
memberikan gambaran mengenai keadaan terkini tentang infeksi ESBL-E yang terfokus pada diagnosis dan
penanganan infeksi tersebut melalui pembahasan beberasa studi mengenai masalah ini.

Kata kunci: resisten multi obat, ESBL, diagnosis, penatalaksanaan.

ABSTRACT
Bacterial resistance to antibiotics is a serious problem worldwide that affect the increment of morbidity
and mortality rate; Enterobacteriaceae producing ESBL is one of the causes. However, there are still limited
information regarding diagnosis and management of ESBL-E infection. Detection of ESBL-E requires certain
steps that are problematic and time consuming. Diagnosis and management of ESBL-E infection have become
more and more challenging due to limited diagnostic method available and choice of antibiotics that may be
used, along with growing subtyped of ESBL through various of mutations. This article is aimed to give an
overview on current situation of ESBL-E infections, with a focus on diagnosis and management of such infection
by reviewing several recent studies on related issue.

Keywords: multi-drug resistant, ESBL, diagnosis, management.

156 Acta Medica Indonesiana - The Indonesian Journal of Internal Medicine

Vol 48 • Number 2 • April 2016 Diagnosis and management of infections caused by Enterobacteriaceae
INTRODUCTION
Bacterial resistance to antibiotics is a serious
problem worldwide. Until recently, many cases
of resistance towards antibiotics are known due
to methicillin-resistant Staphylococcus aureus
(MRSA), vancomycin resistant Enterococci
(VRE), penicillin-resistance Pneumococci,
carbapenem-resistance Acinetobacter baumanni,
multi-resistant Mycobacterium tuberculosis,
and Enterobacteriaceae producing extended-
spectrum β-lactamase (ESBL).1
Production of ESBL is an important
mechanism causing resistance towards 3rd
generation of cephalosporin, such as ceftazidime,
ceftriaxone, and cefotaxime, which is commonly
used, for empirical therapy of antibiotics.
The growing prevalence of infection due
to Enterobacteriaceae producing ESBL
(ESBL-E) cause challenge in treating nosocomial
infection that usually treated empirically with
cephalosporin and fluoroquinolon. Delayed
diagnosis and management are related to high
mortality, hospital cost and length of stay in the
hospital.2,3
Since more than 70% of world populations
live in the Asia-Pacific region, antibiotic
resistance in Asia is also considered as a
global problem. The Study for Monitoring
Antimicrobial Resistance Trends (SMART)
which monitor the pattern of antibiotic resistance
in intra-abdominal infection since 2002 and
urinary tract infection since 2009 until 2011,
found the main multi-resistant bacteria causing
infection are Escherichia coli and Klebsiella
pneumoniae with the prevalence of 47.8% and
14.5% respectively in intra-abdominal infection,
whereas in urinary tract infection are 44.3%
and 11.8% respectively. Moreover, the SMART
study also obtained that highest prevalence of
ESBL-E infection is in Asia, which is more than
40%, followed by Latin America and the Middle
East. The SMART study also showed increasing
pattern of infection by ESBL-E prevalence in
Asia.4,5
The use of broad-spectrum antibiotics,
especially third generation of cephalosporin and
fluoroquinolon leads to the growth of ESBL-E
in hospital and associated with high treatment
failure and mortality. Early control of ESBL-E
in sepsis patients due to nosocomial infection
and adequate treatment is essential in patients’
management.2 This review will discuss about the
diagnosis and management of ESBL.
DEFINITION OF ESBL
Extended spectrum β-lactamase (ESBL) is
an enzyme produced by certain bacteria causing
them to become resistant to several antibiotics
including third generation of cephalosporin and
aztreonam. This enzyme works by hydrolyzing
β-lactam ring in β-lactam antibiotics (BL). It is
carried in the chromosomes of those particular
bacteria and transferred to other populations
of bacteria through plasmid. There are several
ESBL-E known today, including Klebsiella
pneumoniae (ESBL-KP) and Escherichia coli
(ESBL-EC). The ESBL-E infection firstly found
was an infection by K. Pneumonia in Germany
in the year of 1983 and spread to all Europe as
well as America. In Asia, the first infection was
found in China in 1988.6-8
CLASSIFICATION OF ENZYME Β-LACTAMASE
There are many classification schemes
available for enzyme β-lactamase, however the
most commonly used are the Ambler classification
and the Bush-Jacobsky classification. Ambler
classification, was first communicated in 1991,
categorized ESBL into 4 classes, that are A, B,
C, and D based on their amino acid structure,
where class A, C and D have an active side of
serine-β-lactamase and class B have an active
side of metallo-β-lactamase.8,9
The Bush-Jacobsky-Mendeiros was first
introduced in 1989, expanded on 1995 and
renewed to become Bush-Jacobsky classification
in the year of 2009, where β-lactamase enzyme
is categorized into 4 different groups, presented
in Table 1. The first group is cephalosporinase
or AmpC, also known as Ambler class C. It is
more active towards cephalosporin compared
to benzilpenicillin and usually resistant to
clavulanate acid inhibition, also active towards
cephamicin such as cephotixin, and high affinity
toward aztreonam.9
The second group is also known as serine-β-
lactamase. It is the largest group of β-lactamase
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Table 1. Enzyme β-lactamase classification9

Bush- Inhibited by
Molecular
Bush-Jacoby Jacoby- Distinctive Defining Representative
class CA or
group (2009) Medeiros substrate(s) EDTA characteristic(s) enzyme(s)
(subclass) TZBa
group (1995)
1 1 C Cephalosporins No No Greater hydrolysis E.coli AmpC,
of cephalosporins P99, ACT-1,
than benzylpenicillin; CMY-2, FOX-
hysrolyzes 1, MIR-1
cephamycins
1e NIb C Cephalosporins No No Increased hydrolysis GC1, CMY-37
of ceftazidime and
often other oxymino-
b-lactams
2a 2a A Penicillins Yes No Greater hydrolysis of PC1
benzylpenicillin than
cephalosporins
2b 2b A Penicillins, Yes No Similar hydrolysis of TEM-1, TEM-
early benzylpenicillin and 2, SHV-1
cephalosporins cephalosporins
2be 2be A Extended- Yes No Increased hydrolysis TEM-3, SHV-2,
sepctrum of oxymino-b- CTX-M-15,
cephalosporins, lactams (cefotaxime, PER-1, VEB-1
monobactams ceftazidime,
ceftriaxone, cefepime,
aztreonam)
2br 2br A Penicillins No No Resistance to TEM-30, SHV-
clavulanic acid, 10
sulbactam, and
tazobactam
2ber NI A Extended- No No Increased hydrolysis TEM-50
spectrum of oxymino-b-
cephalosporins, lactams combined
monobactams with resistance to
clavulanic acid,
sulbactam, and
tazobactam
2c 2c A Carbenicillin Yes No Increased hydrolysis PSE-1, CARB-
of carbenicillin 3
2ce NI A Carbenicillin, Yes No Increased hydrolysis RTG-4
cefepime of carbenicillin,
cefepime, and
cefpirone
2d 2d D Cloxacillin Variable No Increased hydrolysis OXA-1, OXA-
of cloxacillin or 10
oxacillin
2de NI D Extended- Variable No Hydrolyzes cloxacillin OXA-11, OXA-
spectrum or oxacillin and 15
cephalosporins oxymino-b-lactams
2df NI D Carbapenems Variable No Hydrolyzes cloxacillin OXA-23, OXA-
or oxacillin and 48
carbapenems
2e 2e A Extended- Yes No Hydrolyzes CepA
spectrum cephalosporins.
cephalosporins Inhibited by clavulanic
acid but not
aztreonam
2f 2f A Carbapenems Variable No Increased hydrolysis KPC-2, IMI-1,
of carbapenems, SME-1
oxymino-b-lactams,
cephamycins

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Table 1. Enzyme β-lactamase classification9
Bush-
Molecular
Bush-Jacoby Jacoby- Distinctive
class
group (2009) Medeiros substrate(s)
(subclass)
group (1995)
3a 3 B (B1) Carbapenems
B (B3)
3b 3 B (B2) Carbapenems
NI 4 Unknown
a
CA, clavulanic acid; TZB, tazobactam
b
NI, not included.
enzyme due to its increasing prevalence in
the last 20 years. It belongs to Ambler class
A and D. The third group is also known as
metallo-β-lactamase (MBL), which has unique
structures, and functions, that requires zinc in
their active site, and have the ability to hydrolyze
carbapenem. However, nowadays several serine-
β-lactamase also have this ability. The difference
between them is that MBL has low monobactam
hydrolyzing ability and cannot be inhibited by
clavulanate acid and tazobactam. According to
Ambler classification, they belong to class B. The
fourth group of ESBL is present in the previous
classification of 1995 but has been omitted in the
latest scheme. This enzyme might be categorized
into different classification if sufficient data is
available.8,9
TYPES OF ESBL
The type of ESBL that is commonly found is
Temoneira (TEM). About 90% of E. coli, which
are resistant to ampicillin, occurred due to the
production of TEM-1. This type has the ability
to hydrolyze penicillin and first generation of
cephalosporin but not cephalosporin oxymino.
Although it is usually found in E. coli and K.
pneumonia, frequency of TEM type β-lactamase
is also increasing in other gram-negative bacteria.
Until recently, there are 140 TEM type is known.
The second type is Sulfhydryl variable (SHV)
whose 68% of its amino acid is similar to TEM
type. Most commonly found in K. pneumonia is
Inhibited by
Defining Representative
CA or
EDTA characteristic(s) enzyme(s)
TZBa
No Yes Broad-spectrum IMP-1, VIM-1,
hydrolysis including CerA, IND-1
carbapenems but not
monobactams
L1, CAU-1,
GOB-1, FEZ-1
No Yes Preferential hydrolysis CphA, Sfh-1
of carbapenems
SHV-1 that cause resistance towards penicillin,
tigecycline and piperacillin but not cephalosporin
oxymino. There are 60 SHV type known so far
in Europe, America and in the whole world.
The TEM-1 and SHV-1 type have the ability
to inactivate ampicillin, and some of them may
experience further mutation that will lead to
expansion of β-lactamase activity. This explains
why there are other types of TEM and SHV that
also cause the third generation of cephalosporin
and aztreonam inactivation.10-13
The Cefotaxime hydrolyzing capabilities
(CTX) type has stronger ability in hydrolyzing
cefotaxime, and may be inhibited by tazobactam
as β-lactamase inhibitor. There are more than 80
CTX type known so far. The CTX-M enzyme
is not limited to nosocomial infection only but
have the potency to spread in the community
(usually by E. coli) and this has become a
public health problem. According to a survey in
2000, the prevalence of ESBL-E in community
of European countries has increased. A study
by Ben-Ami et al14 in Israel found that 14% of
ESBL infection have community onset. This
study also showed that there was an increased
risk of infection in nursing homes. Furthermore,
Rodriguez-Bano et al15 did an analysis between
the uses of BL antibiotics and β-lactam inhibitors
(BLI) as a combination compared to carbapenem
in treating infections caused by ESBL-EC in the
year of 2011 towards 103 Spanish patients, and
found that 51% cases occurred in the community
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due to CTX-M. Moreover, Severin et al16 did a
research about the characteristics of ESBL-EC
and ESBL-KP infections in Surabaya and found
that the prevalence of CTX-M-15 in ESBL-EC
is 94.5% and ESBL-KP is 55.6%.11-12
Oxacillin hydrolyzing capabilities (OXA)
β-lactamase is a less commonly found type,
and has different characteristics from TEM
as well as SHV since it belongs to Ambler
class D. This type has the ability to hydrolyze
oxacilin and cloxacillin, and cannot be inhibited
by clavulanate acid. It is mainly found in P.
aeruginosa, mostly in Turkey and France, but
also present in other gram-negative bacteria
such as 1-10% E. coli producing OXA-1.
Several other ESBL that is transmitted through
plasmid, such as Pseudomonas extended
resistant (PER), Vietnam ESBL (VEB), Guiana
extended-spectrum (GES) and integron-borne
cephalosporinase (IBC) are rarely found and
have very limited transmission.10-12
ESBL MECHANISMS OF RESISTANCE
Bacteria may become resistance to β-lactam
antibiotics through several mechanisms. Most
commonly found is through the destruction by
β-lactamase enzyme in the periplasm of gram-
negative bacteria. This enzyme has higher
affinity towards antibiotics than antibiotics to
their target. The binding of this enzyme will
cause β-lactam ring to hydrolyze. The gene
coding β-lactamase is found in the chromosomes
and extra-chromosomes, and usually a mobile
element. This ESBL resistance may be acquired
in a mobile genetic element (such as in K.
pneumoniae and E. coli) or in an immobile
genetic chromosomes (in Enterobacter species),
and have the ability to hydrolyze penicillin and
cephalosporin. One of the strategy to counteract
this mechanism is by using inhibitors that bind
to these enzyme, however inhibitors such as
clavulanate acid, sulbactam and tazobactam do
not bind to all β-lactamase in the chromosomes,
hence cannot fully prevent inactivation of BL
antibiotics by this enzyme. There is no BL/BI
combination known so far has the ability to
inhibit all β-lactamase enzyme.17,18
Other mechanisms include coupling in
gram-negative bacteria where there is reduced
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membrane permeability with fast antibiotics
reflux from periplasm to exterior of the cell.
This mutation will cause decreased amount
of BL antibiotics that goes into the cell, along
with increased amount of channels pumping out
the antibiotics outward. This mechanism also
happens in the resistance of ESBL-E towards
quinolone and aminoglycoside.18
DETECTION OF ESBL
Identification of ESBL-E is a problem in
hospitals and laboratory facilities despite its
importance in therapeutic approach and infection
control to prevent their spread. Most guidelines
recommend specimen screening based on
reduced sensitivity towards cephalosporin and
followed by one of the tests available to confirm
the presence of ESBL-E. However, it is still not
known which method should be used.19
According to National Committee for
Clinical Laboratory Standards (NCCLS);
which is changed into Clinical and Laboratory
Standards Institute (CLSI) in 2005, mentioned
that ESBL screening should be routinely done.
Recommendation by CLSI shows that ESBL
detection is consists of two steps, the first is
screening for reduced sensitivity to certain
antibiotics used such as cefotaxime, ceftriaxone,
ceftazidime, or aztreonam. The next step is to
do a confirmatory test only if positive screening
result is found. The aim of confirmatory test
is to detect hydrolyzing potential by ESBL
towards antibiotics that are used in screening
in the presence of BLI. Several type of tests
are recommended by CLSI, however until now
there is no gold standard examination to detect
ESBL.20-22
Screening test of ESBL may be done using
Vitek, and positive result is when there is a
resistance towards cephalosporin and aztreonam.
Positive or negative result is evaluated using
Advanced Expert System. Moreover, Kirby-
Bauer disks, according to CLSI recommendation,
can also do screening test.23,24
Confirmatory test may be done using double-
disk synergy test (DDST), combination disk
method, or E-test ESBL strip. The DDST test is
performed on agar with a 30 μg disk of cefotaxime
(and⁄or ceftriaxone and⁄or ceftazidime and⁄or
Vol 48 • Number 2 • April 2016 Diagnosis and management of infections caused by Enterobacteriaceae
aztreonam) and a disk of 10μg of clavulanate
acid positioned at a distance of 30 mm (centre
to centre). The test is considered as positive
when a decreased susceptibility to cephalosporin
is combined with a clear-cut enhancement of
the inhibition zone in front of the clavulanate
acid-containing disk (Figure 1). Whereas the
evaluation of combination disk method is by
measuring the inhibition area around disk
containing cephalosporin and disk containing
cephalosporin and clavulanate acid. Usually both
disks are located at a distance of ≥5 mm (centre
to centre), and positive result is when the area
enlarged until 50% (Figure 2). Confirmatory test
may also be done using E-test ESBL strip. Two-
sided strips are used in this method, containing
cefotaxime, cefazidime or cefepim, either
alone at one end of the strip, or combine with
clavulanate acid on the other end. The E-test
ESBL strip is considered as positive when there
is a phatom zone in the lowest concentration
of antibiotic with clavulanate acid or when the
minimum inhibitory concentrations (MIC) is
reduced by more than two-fold in the presence
of clavulanate acid (Figure 3).23
Figure 1. Double-disk synergy test (DDST) method7
Figure 2. Combination disk method24
Figure 3. E-test ESBL strip7
A study by Garrec et al19 in a hospital in
France, compared different phenotype method
in the detection of ESBL-E. It was mentioned
that Vitek is considered as a routine method in
the detection of ESBL with sensitivity 92-93%
and low specificity that is 50-79%. However,
E-test has the sensitivity of 71-73% in testing
cefotaxime and ceftazidim, and 90% for cefepime.
Another method is combination disk methods
with sensitivity 100% in testing cefotaxime and
cefepim towards ESBL-E. Double-disk synergy
method has better sensitivity but the distance of
how the disks should be positioned still need
recommendation by microbiologists.
Phenotype confirmatory tests, as mentioned
before, cannot identify specific enzymes causing
the production of ESBL. Therefore, genotype
confirmatory tests is also important, and may
be done using polymerase chain reaction (PCR)
followed by sequencing to differ variants of
those specific enzymes. Several other methods
include PCR with restriction fragment length
polymorphism analysis (PCR-RFLP) and PCR
with single-strand conformational polymorphism
analysis (PCR-SSCP). Nevertheless, subtypes
of ESBL continue to grow hence these methods
have develop limitation; which made detection
of ESBL become complex and difficult due to
variety of mutation process.
RISK FACTORS OF ESBL COLONIZATION
AND INFECTION
Infections due to ESBL-E are usually
nosocomial and most commonly found in
intensive care units (ICUs), and related to the
length of stay, increased cost and mortality.
Several risk factors mentioned by Park et
al26 in their study on all bacteremia patients
in Korean hospitals since January 2005 until
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Audrey Amelia
March 2009 include geriatrics, diseases such
as liver cirrhosis and malignancy that usually
need long hospital care, airway and urinary
tract infections, use of catheter and naso-gastric
tube (NGT), severe sepsis and use of third
generation of cephalosporin and quinolone in
the last 3 months during hospital stay. Similar
things also communicated by Muro et al27 in their
research among 90 patients in Mexico with ESBL
infections known from their blood culture results,
and found that several risk factors causing this
infection are the use of catheter and intravenous
line, hospital length of stay more than 15 days,
underwent surgery, and use of cephalosporin.
Whereas in a study by Freeman et al28 of
206 patients with culture result of ESBL-EC
and ESBL-KP in 3 different hospitals in New
Zealand from 2009 until 2011, obtained that
patients experienced ESBL-EC usually occur
due to community infection or with chronic
pulmonary infection in high prevalence country.
On the other hand, infection due to ESBL-KP is
usually related to ICU admission, surgery and
transmission within health care facilities.
Recently, several cases of ESBL-E in the
community have been reported. Comparison
of the characteristics and risk factors due to
ESBL-E in the community and nosocomial are
summarized in Table 2.25
MANAGEMENT OF ESBL INFECTIONS
Until recently, choices of antibiotics available
to treat ESBL-E infections are still limited.
According to European antimicrobial resistance
survey in 2011 from culture results that the
prevalence of third generation of cephalosporin
Table 2. Characteristics of ESBL-E infections25
Onset Community acquired
Organism Escherichia coli
Type of ESBL CTX-M (mostly CTX-M15)
Infection Majority is urinary tract infection
Susceptibility Resistance to all penicillin and cephalosporin, also
several other antibiotics including fluoroquinolone
Risk factors Recurrent urinary tract infection, use of broad-
spectrum antibiotics such as cephalosporin,
fluoroquinolone, hospital length of stay, live in
nursing homes, geriatrics, and diabetes mellitus.
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in E. coli and K. pneumoniae are 9.1% and
30.1%; in ESBL-EC is 85-100% and ESBL-KP
is 62.5-100%. Resistance of E. coli towards
carbapenem, quinolone and aminoglycosides
are 0.04%, 20.9% and 9.3% respectively;
whereas resistance of K. pneumoniae towards
carbapenem, quinolone and aminoglycosides are
9.1%, 30.5%, and 26.2%, respectively. Because
resistance towards first line of antibiotics
treatment is increasing, therefore choice of
empirical antibiotic treatment has become more
difficult. Empirical antibiotic treatments should
be based on antibiogram in different institution
and usually varies from one hospital to another
in different city and countries.25,29
Several studies mentioned that cephalosporin
still can be used because ESBL type TEM
and SHV have low MIC towards cefotaxim.
However, CLSI recommends that all ESBL-E
should be considered as resistant to cephalosporin
without considering their MIC because the use of
cephalosporin is related to high treatment failure
and mortality. This is occurred due to inoculum
effect in bacteria with the ability to destroy the
antibiotics. When bacteria die and destroy the
antibiotics at the same time, cellular enzyme
will be released and may reduce antibiotics
concentration. In vitro test to evaluate bacteria’s
ability to counteract antibacterial activity by BL
antibiotics is determined by 2 factors, which
are antibiotics intrinsic activity toward bacteria
tested and antibiotic susceptibility to hydrolyze
β-lactamase enzyme. In general, the higher the
inoculum effect, the easier certain antibiotics to
be hydrolyzed by ESBL.30,31
Hospital acquired
Klebsiella spp
Mostly SHV and TEM
Airway and intra abdominal infection
Resistance to all penicillin and cephalosporin,
also several other antibiotics including
fluoroquinolone
Long hospital length of stay especially in
intensive care units, use of ventilator, catheter
and use of broad-spectrum antibiotics such as
cephalosporin.
Vol 48 • Number 2 • April 2016 Diagnosis and management of infections caused by Enterobacteriaceae
Carbapenem is the choice of treatment in
critically ill patients due to ESBL-E infections,
and usually have lower treatment failure with
better results. Vardakas et al32 analyzed several
studies on comparison between carbapenem
and alternative antibiotics in treating ESBL-E
infection, and found that empirical and definitive
therapy with carbapenem have lower mortality
compared to the use of combination non β-lactam
antibiotics (non-BL) and BLI. Carbapenem, such
as imipenem, meropenem and doripenem are
now commonly used as empirical therapy for
nosocomial infection due to ESBL-E.30,32-33
Infections caused by ESBL is considered as
serious problem in treating infectious patients in
a matter of choosing the appropriate antibiotics,
which leads to increased use of carbapenem that
creates new problem that is Enterobacteriaceae
resistance to carbapenem, which of course
will cause further difficulties in choosing
antibiotics. In order to prevent this carbapenem
resistance, the use of BL/BLI combination has
come into consideration. Combination of BL/
BLI, such as amoxicillin-clavulanate (AMC)
or piperacillin-tazobactam (PTZ) may be used
to handle infection due to ESBL-E. Tamma et
al34 underwent a research in the year of 2007
until 2014 in 213 American patients that were
divided into 2 groups, where the first group was
given PTZ as empirical therapy then switched
to carbapenem in 84 hours and the second group
was treated with carbapenem from the beginning.
A fourteen days mortality analysis was made,
with results of higher mortality rate in the group
initially treated with PTZ. This is different
from a study by Rodriguez-Bano et al15 that
analyze comparison of treatment between BL/
BLI and carbapenem to treat ESBL-EC in 2011
in Spain among 103 patients and displayed that
BL/BLI may be used as alternative treatment.
Comparable results was showed by Vardakas et
al32 dan Shiber et al35 that there is no difference in
mortality rate between carbapenem and BL/BLI.
Until lately, there are still limited publications
on the use of BL/BLI in treating ESBL-E hence
carbapenem is still considered as treatment of
choice.30
Analyses conducted on ESBL infection
produce variety of results. In a study by Kumar
et al36 on 180 patients with ESBL infection in
India, obtained that 100% cases are susceptible
to imipenem. This study also showed ESBL
susceptibility pattern to other anitbiotics such as
PTZ is 87.2%, cefoperazone/sulbactam 76.7%,
AMC 75.55%, ceftazidime/clavulanate 66.11%,
and aminoglycoside that is amikacin 73.17% and
gentamycin 60%.
Fosfomycin is also known to have bactericidal
effect against Enterobacteriaceae. Falagas et
al37 underwent a study on 4448 patients with
ESBL-E infections and acquired that 90% cases
are susceptible to fosfomycin. Based on CLSI
criteria, it was mentioned that ESBL-E are
susceptible 91.3% from 11 studies available.
Fosfomycin given with dosage of 2-4g every
6 hours also can be used to treat K. pneumonia
carbapenemase (KPC) shown in a study by
Michalopoulos et al.38 This also shown by Neuner
et al39 in their study in 41 patients with urinary
tract infection cased by ESBL-E or KPC, and
found that 92% are successfully treated with
fosfomycin.
Nitrofurantoin is considered as another choice
of antibiotics to treat urinary tract infections
caused by ESBL-E. In a study by Tasbakan
et al40 showed that nitrofurantoin has good
clinical response in patients with uncomplicated
urinary tract infection due to ESBL-EC. In a
study by Kulkarni et al24 toward 265 patients
with ESBL (known from culture results), found
that resistance test to nitrofurantoin is 75% and
amikacin is 70.4% whereas gentamycin is only
19.4%. However, there are not enough studies
on the use of nitrofurantion and aminoglycoside
in the management of ESBL-E infection hence
they are still rarely used.
A study by Reinert et al41 as part of TEST
study towards patients in health care centers
of Asia Pacific, North America, America Latin
and Europe, found that about 94.3-97.1%
ESBL-E is susceptible to tigecycline. Whereas
a study by Corvec et al 42 mentioned that
fosfomycin, tigecycline, and colistine can be
use to treat ESBL, however tigecycline cannot
be used as single antibiotic therapy to treat
infections caused by gram-negative bacteria. If
combined with colistine, tigecycline may give
out better result in infection due to ESBL-KP
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and MBL. This, of course, will make tigecycline
a choice of treatment in managing ESBL-E
infection. However, tigecycline is commonly
used in treating MRSA and also infection due
to carbapenem-resistant bacteria hence it is not
recommended as a first line antibiotic.43
In Indonesia, Kuntaman et al44 did a study
on susceptibility pattern of ESBL towards
commonly used antibiotics in 300 ESBL infected
patients in Surabaya and Malang in 2010.
Sensitivity of ESBL-EC and ESBL-KP towards
meropenem was 100% and 96.5% respectively,
towards cefoperazone-sulbactam, were 97.7%
and 94.4%, towards fosfomycin were 95.3%
and 94.4%, towards amikacin were 90.6% and
86.6%, towards ciprofloxacin were 26.6% and
53.3%, whereas towards cefotaxime were 3.22%
and 4.23% respectively. From those data, it
can be concluded that meropenem is the main
choice of therapy in managing infection due
to ESBL-E, however fosfomycin, combination
of BL/BLI and amikacin can also be used.
Treating those patients with cephalosporin and
fluoroquinolon should be prohibited, based on
CLSI recommendation even if they seem to be
sensitive in the culture results.
PREVENTION
Increasing of ESBL-E may happen easily
within hospital environment, especially through
medical staffs contaminated hands that will
extent infection between patients. Distribution
can also occur through health equipment, such
as thermometer, endoscopy instruments and
bath utensils. Consequently, when and how to
perform steps of washing hands properly and
how to sterilized medical apparatus should be
applied in daily clinical practices. Hospitals
have the responsibility suppress the incidence
of ESBL-E infection one of which by isolating
infected patients to prevent further spread.45
High prevalence of antibiotic resistance
and inadequate choice of available antibiotics
necessitate clinicians to use antibiotic wisely.
Antimicrobial stewardship program (ASP)
improve antibiotic use by shortens the duration
of antibiotic therapy, limits the use of broad-
spectrum antibiotics and monitors appropriate
use of antibiotic. Nowadays, Centers for
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Acta Med Indones-Indones J Intern Med
Disease Control and Prevention (CDC) have
recommended ASP availability in every
hospital.46
CONCLUSION
Infection due to bacteria that resistant
to multiple antibiotics is a rising worldwide
problem, particularly nosocomial infection
caused by ESBL-E. The prevalence of ESBL-E
continues to increase, mainly in Asian countries.
Detection of ESBL-E infection requires
complex evaluation, consists of screening and
confirmation. However, subtypes of ESBL-E
keep growing thus methods available have
become restricted; which cause detection to
be even more challenging due to variety of
mutations. This will of course make choosing
antibiotic becomes problematic. Most studies
show great results with carbapenem therapy,
nevertheless, other antibiotics, for example BL/
BLI combination, like PTZ, and fosfomycin also
show good results, so they can also be used to
treat ESBL-E infection. Carbapenem should only
be used in serious and life threatening infections
in order to reduce carbapenem resistant, even if
it still rarely found, particularly in Asia.
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